Toluene → (3R)-3-fluoro-N-(5-methyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxamide

HRID 390705노트

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HRID 390705 반응식
[CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8](Cl)(Cl)=[O:9].C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl.[F:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1>ClCCl>[F:29][C@@H:30]1[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:9])[CH2:31]1

참가 물질

7

반응물 5

HCID 1140TolueneHCID 6371PhosgeneHCID 81531DiisopropylethylamineHCID 3517702-Amino-5-methylthiazoleHCID 2759162(3R)-3-fluoropyrrolidine hydrochloride

생성물 1

HCID 86631926(3R)-3-fluoro-N-(5-methyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxamide

시약·촉매·용매 1

HCID 6344Dichloromethane용매

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온도
-45 °C

실험 절차

5-Methylthiazol-2-amine (2.28 g, 20.0 mmol) was dissolved into dichloromethane (200 mL) and cooled to near −50° C. 20% Phosgene in toluene (12.6 mL, 24 mmol) was added rapidly over less than 30 seconds and stirred for 10 minutes more at −45° C. before the addition of diisopropylethylamine (17.4 mL, 100 mmol). The mixture was stirred for another 30 minutes near −45° C., (R)-3-fluoropyrrolidine hydrochloride (5.02 g, 40 mmol) was added, and after five minutes the cold bath was removed and the reaction warmed slowly to room temperature. The solution was quenched and stirred thoroughly with concentrated aqueous ammonium hydroxide (25 mL). The aqueous phase was separated and extracted with dichloromethane, and the combined organic phases were washed twice with water; each aqueous phase was back-extracted with dichloromethane. The combined organic phases were concentrated and then slurried in 3:1 hexanes/ethyl acetate. The solids were collected by filtration, rinsed with more 3:1 hexanes/ethyl acetate, and then slurried and rinsed first with 3:1 hexanes/dichloromethane, and then with 1:1 hexanes/dichloromethane to give the title compound.

후처리

  1. temperaturecooled
  2. customto near −50° C
  3. customafter five minutes the cold bath was removed
  4. temperaturethe reaction warmed slowly to room temperature
  5. customThe solution was quenched
  6. stirringstirred thoroughly with concentrated aqueous ammonium hydroxide (25 mL)
  7. customThe aqueous phase was separated
  8. extractionextracted with dichloromethane
  9. washthe combined organic phases were washed twice with water
  10. extractioneach aqueous phase was back-extracted with dichloromethane
  11. concentrationThe combined organic phases were concentrated
  12. filtrationThe solids were collected by filtration
  13. washrinsed with more 3:1 hexanes/ethyl acetate
  14. washrinsed first with 3:1 hexanes/dichloromethane

출처 및 근거

ORD 기록
ord-6b47dbc0c7cc44919c7c3b535ba035c3
출처 데이터셋
uspto-grants-2013_02
특허 번호
US08383657B2

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